Alzheimer's Disease (AD) is a neurodegenerative disorder associated with the loss of cognitive function and the presence of characteristic neuropathological changes that include synaptic and neuronal loss, neurofibrillary tangles and extracellular senile plaques composed of beta-amyloid (Abeta) protein deposits. The association of complement proteins, as well as acute phase proteins and reactive glia, with senile plaques in AD brain suggests that inflammatory processes may play a role in this disease, and that complement activation may contribute to the initiation of these inflammatory events. However, the actual in vivo contribution of complement activation to pathology and dementia in AD has not yet been determined. Our recently completed study provides compelling evidence for a detrimental role for C1q (the initiation component of the classical complement pathway) in the progression of pathology in murine models of Alzheimer's Disease. Animals overexpressing the amyloid precursor protein but lacking the ability to activate the classical complement pathway showed less inflammation and less loss of critical neuronal structures than those with a functioning classical complement pathway. Since sites of interaction between fibrillar Abeta and C1q critical for this activation are known, the development of potential therapies that would block the amyloid interaction with C1q that leads to complement activation should be feasible. The research program described here focuses on the generation of animal models of AD that more closely and critically mimic the human disease. The models will be genetically manipulated to either eliminate or enhance specific features of the complement system, and the age-related consequences on brain pathology and behavior compared. These novel models will test the hypothesis that complement activation promotes the progression of pathology and cognitive dysfunction in AD at a stage when fibrillar Abeta is present, and will be valuable for testing candidate therapies for AD in an in vivo context that more closely mimics the human condition.